Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults
Authors: Skylar Walters, Alex G. Contreras, Jaclyn M. Eissman, Shubhabrata Mukherjee, Michael L. Lee, Seo-Eun Choi, Phoebe Scollard, Emily H. Trittschuh, Jesse B. Mez, William S. Bush, Brian W. Kunkle, Adam C. Naj, Amalia Peterson, Katherine A. Gifford, Michael L. Cuccaro, Carlos Cruchaga, Margaret A. Pericak-Vance, Lindsay A. Farrer, Li-San Wang, Jonathan L. Haines, Angela L. Jefferson, Walter A. Kukull, C. Dirk Keene, Andrew J. Saykin, Paul M. Thompson, Eden R. Martin, David A. Bennett, Lisa L. Barnes, Julie A. Schneider, Paul K. Crane, Timothy J. Hohman, Logan Dumitrescu, Erin Abner, Perrie Adams, Alyssa Aguirre, Marilyn Albert, Roger Albin, Mariet Allen, Lisa Alvarez, Liana Apostolova, Steven Arnold, Sanjay Asthana, Craig Atwood, Gayle Ayres, Robert Barber, Lisa Barnes, Sandra Barral, Jackie Bartlett, Thomas Beach, James Becker, Gary Beecham, Penelope Benchek, David Bennett, John Bertelson, Sarah Biber, Thomas Bird, Deborah Blacker, Bradley Boeve, James Bowen, Adam Boxer, James Brewer, James Burke, Jeffery Burns, William Bush, Joseph Buxbaum, Goldie Byrd, Laura Cantwell, Chuanhai Cao, Cynthia Carlsson, Minerva Carrasquillo, Kwun Chan, Scott Chase, Yen-Chi Chen, Marie-Franciose Chesselet, Nathaniel Chin, Helena Chui, Jaeyoon Chung, Suzanne Craft, Paul Crane, Carlos Cruchaga, Michael Cuccaro, Jessica Culhane, C. Munro Cullum, Eveleen Darby, Barbara Davis, Charles DeCarli, John DeToledo, Dennis Dickson, Nic Dobbins, Ranjan Duara, Nilufer Ertekin-Taner, Denis Evans, Kelley Faber, Thomas Fairchild, Daniele Fallin, Kenneth Fallon, David Fardo, Martin Farlow, John Farrell, Lindsay Farrer, Victoria Fernandez-Hernandez, Tatiana Foroud, Matthew Frosch, Douglas Galasko, Adriana Gamboa, Daniel Geschwind, Bernadino Ghetti, Alison Goate, Thomas Grabowski, Neill Graff-Radford, Anthony Griswold, Jonathan Haines, Hakon Hakonarson, Kathleen Hall, James Hall, Ronald Hamilton, Kara Hamilton-Nelson, Xudong Han, John Hardy, Lindy Harrell, Elizabeth Head, Victor Henderson, Michelle Hernandez, Lawrence Honig, Ryan Huebinger, Matthew Huentelman, Christine Hulette, Bradley Hyman, Linda Hynan, Laura Ibanez, Philip De Jager, Gail Jarvik, Suman Jayadev, Lee-Way Jin, Kimberly Johnson, Leigh Johnson, Gyungah Jun, M. Ilyas Kamboh, Moon II Kang, Anna Karydas, Gauthreaux Kathryn, Mindy Katz, John Kauwe, Jeffery Kaye, C. Dirk Keene, Benjamin Keller, Aisha Khaleeq, Ronald Kim, Janice Knebl, Neil Kowall, Joel Kramer, Walter Kukull, Brian Kunkle, Amanda Kuzma, Frank LaFerla, James Lah, Eric Larson, Melissa Lerch, Alan Lerner, Yuk Ye Leung, James Leverenz, Allan Levey, Donghe Li, Andrew Lieberman, Richard Lipton, Oscar Lopez, Kathryn Lunetta, Constantine Lyketsos, Douglas Mains, Jennifer Manly, Logue Mark, David Marquez, Daniel Marson, Eden Martin, Eliezer Masliah, Paul Massman, Arjun Masukar, Richard Mayeux, Wayne McCormick, Susan McCurry, Stefan McDonough, Ann McKee, Marsel Mesulam, Jesse Mez, Bruce Miller, Carol Miller, Charles Mock, Abhay Moghekar, Thomas Montine, Edwin Monuki, Sean Mooney, John Morris, Shubhabrata Mukherjee, Amanda Myers, Adam Naj, Trung Nguyen, Sid O'Bryant, Kyle Ormsby, Marcia Ory, Raymond Palmer, Joseph Parisi, Henry Paulson, Valory Pavlik, David Paydarfar, Victoria Perez, Margaret Pericak-Vance, Ronald Peterson, Marsha Polk, Liming Qu, Mary Quiceno, Joseph Quinn, Ashok Raj, Farid Rajabli, Vijay Ramanan, Eric Reiman, Joan Reisch, Christiane Reitz, John Ringman, Erik Robertson, Monica Rodriguear, Ekaterina Rogaeva, Howard Rosen, Roger Rosenberg, Donald Royall, Mary Sano, Andrew Saykin, Gerard Schellenberg, Julie Schneider, Lon Schneider, William Seeley, Richard Sherva, Dean Shibata, Scott Small, Amanda Smith, Janet Smith, Yeunjoo Song, Salvatore Spina, Peter St George-Hyslop, Robert Stern, Alan Stevens, Stephen Strittmatter, David Sultzer, Russell Swerdlow, Jeffery Tilson, Giuseppe Tosto, John Trojanowski, Juan Troncoso, Debby Tsuang, Otto Valladares, Jeffery Vance, Vivianna Van Deerlin, Linda Van Eldik, Badri Vardarajan, Robert Vassar, Harry Vinters, Jean Paul Vonsattel, Li San Wang, Sandra Weintraub, Kathleen Welsh-Bohmer, Nick Wheeler, Ellen Wijsman, Kirk Wilhelmsen, Scott Williams, Benjamin Williams, Jennifer Williamson, Henrick Wilms, Thomas Wingo, Randall Woltjer, Martin Woon, Steven Younkin, Lei Yu, Yi Zhao, Xiongwei Zhou, Congcong Zhu, Olusegun Adegoke, Paul Aisen, Liana G. Apostolova, Miriam Ashford, Laurel Beckett, Marie Bernard, Haley Bernhardt, Bret Borowski, Yuliana Cabrera, Nigel J. Cairns, Maria Carrillo, Kewei Chen, Mark Choe, Taylor Clanton, Godfrey Coker, Cat Conti, Karen Crawford, Sandhitsu Das, Michael Donohue, Adam Fleisher, Derek Flenneiken, Evan Fletcher, Juliet Fockler, Arvin Forghanian-Arani, Tatiana M. Foroud, Nick C. Fox, Erin Franklin, Devon Gessert, Hector González, Robert C. Green, Jeffery Gunter, Danielle Harvey, Lindsey Hergesheimer, Carole Ho, Erin Householder, John K. Hsaio, Clifford R. Jack, Jonathan Jackson, William Jagust, Neda Jahanshad, Gustavo Jimenez, Chengshu Jin, David Jones, Kejal Kantarci, Zaven Khachaturian, Alexander Knaack, Robert A. Koeppe, Adrienne Kormos, Susan Landau, Payam Mahboubi, Ian Malone, Donna Masterman, Chet Mathis, Garrett Miller, Tom Montine, Shelley Moore, John C. Morris, Scott Neu, John Neuhaus, Kwangsik Nho, Talia M. Nir, Rachel Nosheny, Kelly Nudelman, Ozioma Okonkwo, Richard J. Perrin, Jeremy Pizzola, William Potter, Michael Rafii, Rema Raman, Robert Reid, Eric R. Reiman, Shannon L. Risacher, Stephanie Rossi Chen, Laurie Ryan, Jennifer Salazar, Andrew J. Saykin, Christopher Schwarz, Matthew Senjem, Elizabeth Shaffer, Leslie M. Shaw, Li Shen, Nina Silverberg, Stephanie Smith, Lisa Taylor-Reinwald, Leon Thal, Sophia I. Thomopoulos, Paul Thompson, Arthur W. Toga, Duygu Tosun-Turgut, John Q. Trojanowski, Diana Truran Sacrey, Dallas Veitch, Prashanthi Vemuri, Sarah Walter, Chad Ward, Michael W. Weiner, Kristi Wilmes, Paul A. Yushkevich, Caileigh Zimmerman
Journal: JAMA Neurology (2023)

Importance Sex differences are established in associations between apolipoprotein E ( APOE ) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, Setting, and Participants This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main Outcomes and Measures Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; P = 9.6 × 10 −7 ), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and Relevance In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.